Neutrophil heterogeneity in anti-neutrophil cytoplasm antibody associated vasculitis

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ANCA associated vasculitis (AAV) is a type of autoimmune disease. Autoimmunity occurs when our immune system, which normally fights infection, instead recognises parts of our own bodies as 'foreign' instead of 'self'. In AAV this leads to inflammation of small blood vessels, known as vasculitis. Blood vessels in many different parts of the body can be affected, including the gut, skin, nerves, lung and kidneys. The condition is often life-threatening, due to severe bleeding in the lungs or inflammation of the kidneys. Even with treatment, patients may develop kidney failure requiring long-term dialysis treatment. We know that neutrophils (a type of white blood cell) are very important in AAV. Patients with AAV make antibodies, called ANCA, that activate neutrophils leading them to damage blood vessels. Until recently neutrophils were thought of as a simple cell type with a short life span and the sole purpose of fighting infection. However, recent research has shown that not all neutrophils are the same and there may be many different types with different functions and purpose. In my preliminary studies, I have found different types of neutrophil in the blood of patients with untreated AAV, that look and behave differently compared to neutrophils from healthy individuals. It is not clear, however, what causes these cells to develop in patients with AAV or if they have an important role in causing the disease. AAV is a life-long condition and both the disease and its treatment often lead to the development of significant complications such as diabetes, infection, cancer or heart disease. The condition has a significant impact on the quality of life of affected patients and relapse (return of the disease after successful treatment) is a major concern. Patients have identified that it feels like they are on a 'knife-edge', caught between continuing immunosuppressive treatment (with potentially serious risks such as infection or cancer) versus risk of relapse with weaning of treatment. Some patients with AAV are more likely to relapse than others and although we do not fully understand why, it may in part be due to different types of antibodies (ANCA) causing disease. There is an urgent need for more specific treatments for AAV and for a better understanding of why some patients relapse and others do not. I suggest that differences in neutrophil subtypes may explain why the condition behaves differently between patients with AAV with different ANCA.In this Fellowship, I plan to fully understand the different types of neutrophil present in AAV and will use several methods to do this, including analysis of genes, proteins on the cell surface, and physical features (e.g. size, shape, stiffness) as cells which are stiffer are more likely to become lodged in and damage small blood vessels. I will isolate patient neutrophils from blood and investigate if they function differently from healthy neutrophils focussing on the capacity of the cells to damage blood vessels. Using tissue (leftover from when patients have a biopsy to diagnose vasculitis) I will use a new technique which allows me to look at the genetic make-up of neutrophils present in the tissues. This will enable me to see if the same cells I identify in blood are present at tissue sites of inflammation in vasculitis. Finally using a rat model of vasculitis I will investigate whether targeting neutrophils directly might be an effective treatment for vasculitis. My initial experiments will focus on preventing neutrophils becoming lodged in tissues by making them softer. My aim is that by significantly increasing our understanding of why patients get AAV and why the condition behaves differently between patients we will be able to target these cells leading to better treatments for patients which are 'personalised' to the type of AAV they have. I hope that this work will directly lead on to clinical studies with the potential for direct benefit to patients.